Abstract 1630: Development of a prodrug for treating renal cancer carcinoma
Authors: Ross Hamilton, Leniher Castan, Stephanie Vega, Atul Varadhachary, Dev Chatterjee
Journal: Cancer Research (2023)

Abstract Improved characterization of the etiology and biology of cancer cells have led to the development of targeted chemotherapeutics, which rely on alterations of particular molecules in cancer cells to exert therapeutic effects. As heterogeneity is an important characteristic of cancer, precision medicine has become a core strategy in treating cancer patients. One approach for targeted therapeutics is the delivery of prodrugs designed to be activated by tumor-associated enzymes (TAEs). SULT1A1, a sulfotransferase enzyme, is overexpressed in about 5-15% of cancer patients including breast, prostate, and renal cell carcinoma (RCC); however, it is either not expressed or expressed at low levels in most normal tissue. Bioinformatic analyses revealed that SULT1A1 overexpression in tumors is correlated with worse patient prognosis. We have identified a new compound, FIS103, which is a small molecule anti-cancer prodrug that is activated by SULT1A1. This class of compounds, N-benzyl indole carbinols (N-BICs), cause rapid cell death by inducing widespread non-specific covalent alkylation of proteins in the cancer cell. Here, we show FIS103, an N-BIC analog, has potent antitumor activity in SULT1A1 high-expressing RCC cell lines (A498 and Caki-1) and has no effect in the SULT1A1 low-expressing cells (786-O and ACHN), indicating low toxicity in the absence of SULT1A1. In silico modeling validated the SULT1A1-FIS103 interaction. Furthermore, FIS103 demonstrates potent SULT1A1-dependent antitumor activity in NU/J mouse xenografts injected with A498 (RCC) cells. Remarkably, the tumors in mice became non-detectable 14 days post-FIS103 treatment and remained absent through the study conclusion (41 days). Since only a subset of patients will express this enzyme, it is critical to identify those who are more likely to respond. Thus, a companion diagnostic to screen for patients whose tumors overexpress SULT1A1 is essential to the success of this approach. Collectively, targeted therapeutics aims to ultimately move patient care away from broadly toxic, non-specific chemotherapies, and towards more rationally designed treatments. By developing our drug and the companion diagnostic, we believe we can provide an effective therapeutic option for the treatment of cancers in a subset of patients who fail standard chemotherapy - either as a standalone therapy, or in rationale combination with other drug options. Therefore, the development of FIS103 has the potential to improve survival as well as quality of life of RCC patients and may have application in other SULT1A1 expressing cancers. Citation Format: Ross Hamilton, Leniher Castan, Stephanie Vega, Atul Varadhachary, Dev Chatterjee. Development of a prodrug for treating renal cancer carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1630.